Abstract 2930: ADG153, a novel masked anti-CD47 IgG1 SAFEbody, demonstrates strong in vivo anti-tumor activities in preclinical solid tumor models and preferential CD47 target engagement in the tumor microenvironment
Authors: Aaron Nguyen, Peng Zou, Songmao Zheng, Jianfeng Shi, Guizhong Liu, Yan Li, Felix Du, Peter Luo, Jiangchun Xu
Journal: Cancer Research (2023)

Abstract Background: Anti-CD47 therapies have demonstrated promising clinical activities; however, expression of CD47 on many different normal human cell types, including RBCs, serves as a large antigen sink for anti-CD47 antibodies. Blocking CD47 on RBCs, such as by magrolimab, has led to anemia, requiring a priming and maintenance dosing schedule in the clinic. ADG153 is a highly differentiated masked anti-CD47 SAFEbody in IgG1 isotype with enhanced ADCC and ADCP functions, in contrast to magrolimab of IgG4 isotype that lacks ADCC and has weaker ADCP effector functions. In normal tissues, the SAFEbody masking moiety is expected to shield ADG153 from binding to CD47; however, in the presence of highly upregulated CD47 in protease-rich tumor microenvironment (TME), the masked antibody can engage dynamically with highly expressed CD47 and can be cleaved, enabling efficient binding to CD47, blocking CD47/SIRPα signaling, and triggering strong anti-tumor activities in solid tumors. Methods: The in vivo anti-tumor efficacy of ADG153 or magrolimab analog (magrolimab) was assessed across several solid tumor xenograft models. Human CD47/SIRPα knock-in mice, harboring CD47-positive xenograft tumors, were used to determine CD47 receptor occupancy (RO) on normal tissues vs. tumors following dosing with ADG153 or magrolimab. Results: ADG153 monotherapy demonstrated strong anti-tumor activities in SCID mice in multiple solid tumor xenograft models, including gastric cancer, SCLC, TNBC, and ovarian cancer models, with mean tumor growth inhibition (TGI) ranging from 75%-99%. Notably, in 2 of these models, the ADG153 efficacy was significantly stronger than that of magrolimab at the same dose level, supporting the importance of IgG1 in introducing ADCC- and ADCP-mediated solid tumor killing effects. In the human CD47/SIRPα knock-in xenograft mouse model, ADG153 and magrolimab dosing resulted in &amp;lt;10% and ~75% CD47 RO on RBCs, respectively. Magrolimab dosing resulted in high RO on normal tissues, but very low RO on tumors. In contrast, ADG153 treatment resulted in low RO on the majority of the normal tissues and RO higher than that achieved by magrolimab on tumors, consistent with the significantly dampened antigen sink liabilities for the masked ADG153. Conclusion: ADG153 demonstrates significantly reduced antigen sink liabilities and favorable CD47 engagement in the TME, which are highly differentiated from other anti-CD47 agents. ADG153 is locally enriched and efficiently cleaved in tumors, engages its target, and elicits potent anti-tumor activities in multiple solid tumor xenograft models. These results indicate that the ADG153 SAFEbody is a novel anti-CD47 IgG1 antibody prodrug with strong ADCC and ADCP capacities and substantially reduced liabilities, supporting its advancement into clinical development. Citation Format: Aaron Nguyen, Peng Zou, Songmao Zheng, Jianfeng Shi, Guizhong Liu, Yan Li, Felix Du, Peter Luo, Jiangchun Xu. ADG153, a novel masked anti-CD47 IgG1 SAFEbody, demonstrates strong in vivo anti-tumor activities in preclinical solid tumor models and preferential CD47 target engagement in the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2930.